O35Stem cells and the origin of prostate cancer

In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. In our studies, we have shown that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3.1 , marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells which express Nkx3.1 in the absence of testicular androgens (castration-resistant Nkx3.1-expressing cells, CARNs) are bipotential and can self-renew in vivo , while single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3.1 mutant mice in serial prostate regeneration assays suggest that Nkx3.1 is required for stem cell maintenance. Finally, targeted deletion of the Pten tumor suppressor gene in CARNs results in rapid formation of carcinoma following androgen-mediated regeneration. These observations indicate that CARNs represent a novel luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer. In our ongoing work, we are investigating the properties of CARNs as cells of origin for prostate cancer. We will present our recent findings and discuss their implications with respect to the relationship between epithelial progenitor populations, prostate cancer initiation, and putative cancer stem cells.